Thrombotic Thrombocytopenic Purpura

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Continuing Education Activity

Thrombotic thrombocytopenic purpura (TTP) is a type of microangiopathic hemolytic anemia that is classically characterized by the pentad of fever, hemolytic anemia, thrombocytopenia, renal dysfunction, and neurologic dysfunction. TTP results from either a congenital or acquired decrease or absence of the enzyme a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13 (ADAMTS13). Low levels of ADAMTS13 results in microthrombi formation which leads to end-organ ischemia and damage. The central nervous system and kidneys are the two most common organ systems affected by TTP. This activity reviews the evaluation and management of patients with thrombotic thrombocytopenic purpura and highlights the role of interprofessional team members in collaborating to provide well-coordinated care and enhance outcomes for affected patients.

Objectives:

  • Outline the characteristic pentad associated with thrombotic thrombocytopenic purpura.
  • Describe the evaluation of thrombotic thrombocytopenic purpura.
  • Summarize management strategies for thrombotic thrombocytopenic purpura.
  • Explain the importance of enhancing care coordination among the interprofessional team to ensure proper evaluation and management of thrombotic thrombocytopenic purpura.

Introduction

Thrombotic Thrombocytopenic Purpura (TTP) is a type of microangiopathic hemolytic anemia that classically has been characterized by the pentad of fever, thrombocytopenia, hemolytic anemia, renal dysfunction, and neurologic dysfunction. TTP results from either a congenital or acquired decrease or absence of the enzyme "a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13"  (ADAMTS13). Low levels of ADAMTS13 results in microthrombi formation which leads to end-organ ischemia and damage. [1][2][3]   This is due to the inability of the ADAMTS13 to inactivate the amount of large multimer-vwf that is necessary to prevent spontaneous coagulation.  Unchecked, the large multimers have a tremendous avidity to bind platelets and initiate thrombi formation.  The central nervous system (CNS) and kidneys are the two most common organ systems affected by TTP. Diagnosis is very important because TTP is a medical emergency which, without treatment, has a mortality of about 90%. About 80% of patients respond to initial treatment; the post-treatment mortality is 10-15%. 

Etiology

TTP results from a decrease or absence of the enzyme ADAMTS13. TTP can be either congenital or acquired. Acquired TTP is more common than the congenital type and is caused by autoantibodies targeting ADAMTS13. Antiplatelet drugs, immunosuppressive agents, HIV, estrogen-containing birth control, and pregnancy are the most commonly listed triggers for ADAMTS13 autoantibody formation causing acquired TTP. The less common congenital form of TTP results from mutations to ADAMTS13. [4][5]

Epidemiology

TTP is a rare disease; the exact prevalence is not clear. Studies cite incidences between 1 and 13 cases per million people depending on geographic location. TTP most often occurs after 40 years of age, but congenital forms can occur in children. TTP is more common in women with a 2:1 female to male predominance. [6]The mortality in TTP without treatment is 90%, but this drops to a mortality of 10% to 20% with proper treatment. However, even with successful treatment relapse occurs in up to 36% of patients. 

Pathophysiology

A deficiency of ADAMTS13 that is caused by gene mutations or acquired autoantibodies is central to the pathophysiology of TTP. The ADAMTS13 enzyme is responsible for breaking down ultra-large VWF multimers. When ADAMTS13 is deficient, large Von Willebrand Factor (VWF) multimers accumulate leading to platelet aggregation, hemolysis, and microthrombi formation. [7][8]  The microthrombi cause ischemia is leading to damage to end organs, with the most common being the central nervous system (CNS) and kidneys. Thrombocytopenia results from platelet consumption during thrombus formation. Anemia results from hemolytic destruction of red blood cells as they pass through small vessels that are partially occluded by thrombi.

History and Physical

Signs and symptoms of TTP that reflect the underlying end-organ damage include thrombocytopenia and hemolytic anemia. The CNS is the most commonly affected end-organ, with manifestations that can include a headache, focal neurologic deficits, seizures, confusion, and vertigo. Signs and symptoms associated with volume overload and/or cardiac arrhythmias can occur due to TTP causing acute renal failure. Hemolytic anemia can cause fatigue, dyspnea, and jaundice. The thrombocytopenia can present as mucosal bleeding as well as petechial and/or purpuric skin findings. Many patients present with a fever. 

Frequently, the presentation of TTP is somewhat indolent. Most cases are discovered in the ambulatory setting after a period of days to weeks that the patient feels poorly. 

Although renal failure is part of the classic presentation, in practice, it is rare to have renal dysfunction. Some providers recommend looking for other causes of TMA that can present with renal failure (HUS); that is, the presence of renal failure suggests against TTP. In addition, if the patient presents with a coagulopathy, it is unlikely to be a patient with TTP.

Evaluation

The classic TTP pentad of fever, thrombocytopenia, hemolytic anemia, renal dysfunction, and neurologic dysfunction cannot be relied on for diagnosis because it only occurs in 50% of cases. Laboratory evaluation plays a critically important role in the diagnosis of TTP because signs and symptoms are variable and end-organ damage can be delayed. For diagnosis, the labs must show anemia and thrombocytopenia along with an indication of active hemolysis, such as the presence of schistocytes, increased unconjugated bilirubin, increased reticulocyte count, increased lactate dehydrogenase, and decreased haptoglobin.[9][10][11]

If renal dysfunction is present, labs often show increased serum creatine, proteinuria, and hematuria. PT and PTT will be normal which differentiates TTP from disseminated intravascular coagulation. ADAMTS13 activity assay should be ordered, but results will not be immediately available. The findings of thrombocytopenia, anemia, and schistocytes, in the absence of DIC, is all that is needed for the presumptive diagnosis of TTP. Once TTP is confirmed, serologic testing should be ordered for autoantibodies, viral hepatitis, and HIV. In females able to bear children, a pregnancy test should be obtained. 

Treatment / Management

The mainstay of treatment in TTP is plasma exchange (PEX) with high-dose steroids (1 mg/kg of prednisone, advised by James George of Oklahoma University). Steroids operate by decreasing the activity of the reticuloendothelial system as well as decreasing autoantibody production. This should be initiated as soon as possible on all patients who have unexplained hemolytic anemia and thrombocytopenia with a normal PT/INR and PTT. Both the ultra-large VWF multimers and the ADAMTS13 autoantibodies are effectively removed from circulation by plasma exchange therapy. Fresh frozen plasma (FFP) is the blood product of choice for plasma exchange.  Other treatments used include splenectomy, cyclosporine, cyclophosphamide, vincristine, and rituximab.[12][13][14]   These are typically adjunctive agents - given when first-line therapy (PEX / steroids) fail.  Splenectomy removes a major site of antibody production and complex assimilation.  It is a major intervention with results that have been quoted as "variable" in terms of efficacy.  Rituximub is an anti-CD20 monoclonal antibody found to help TTP refractory to PEX.  It targets B-lymphocytes and has a good response rate in refractory and relapsed TTP.  It has gained more favor than other agents.  Vincristine, cyclophosphamide, and cyclosporine are immunosuppressive agents with a less than exemplary showing, and for this reason, they are usually given concurrently with other secondary therapies.  A newer agent, Caplacizumab, has a high potential for the treatment of TTP.  It is a nanobody that attacks the A1 section of VWF and thereby prevents platelet adhesion. [15]  In recent clinical studies, Caplacizumab has been shown to have a more rapid onset of action compared to most agents.  With the use of this agent, deaths have been significantly decreased and some experts do advocate its use as a frontline modality.  A packed red blood cell (PRBC) transfusion can be given if there is a clinical indication. Platelet transfusion is controversial but is considered to be contraindicated unless major bleeding is present. A hematologist should be consulted as soon as the diagnosis is considered.  [16]

Monitoring for response is essential to determine the duration of plasma exchange. Typically, hemolysis markers are checked daily. Plasma exchange usually is stopped once the platelet levels stabilize at above 150 for more than 48 hours.[17]

Special Situation

Plasma exchange, coupled with steroids, should be considered the first, the foremost intervention in TTP.  However, the condition of a patient with acute TTP may deteriorate suddenly and rapidly and therefore it is wise to initiate therapy with the initial SUSPICION of the diagnosis.  This may be before any definitive testing has returned.  Additionally, should circumstances arise that acute TTP is suspected but PEX is not readily available, plasma infusion should be started and used as a stop gap measure. [18][19] Because of the severity of it's presentation it is advocated that patients with acute TTP be placed in the intensive care unit setting. [20] This is particularly true where the patient has the involvement of thrombi within the coronary arteries giving rise to dysrhythmias and the risk of sudden death.  Studies have shown that plasma infusion, especially at high-dose, can provide the necessary ADAMTS13 needed as a temporizing measure until PEX is established.  Side effects, such as fluid overload, can be handled by the PEX.  

Differential Diagnosis

  • Cancer-associated TMA
  • Disseminated intravascular coagulation
  • Drug-induced TMA
  • Haemopoietic  transplant-associated TMA
  • Hypertension
  • Immune thrombocytopenia
  • Malignant hypertension

Pearls and Other Issues

Remember that all thrombotic microangiopathies (TMAs) cause microangiopathic hemolytic anemia (MAHA) and thrombocytopenia, but not all findings of MAHA with thrombocytopenia are a result of a TMA syndrome. Other causes of MAHA with thrombocytopenia include:

  • HELLP syndrome (breakdown of red blood cells, hemolysis, elevated liver enzymes, and low platelet count occurring in pregnancy) and severe preeclampsia
  • Severe hypertension (hypertensive emergency)
  • Severe sepsis and disseminated intravascular coagulation (will have abnormal coagulation studies, while TTP will have normal coagulation studies)
  • Cancer
  • Autoimmune processes (lupus, scleroderma, heparin-induced thrombocytopenia, hemophagocytic lymphohistiocytosis
  • Mechanical causes (transjugular intrahepatic portosystemic shunt, cardiac valvular pathology)
  • Paroxysmal nocturnal hemoglobinuria
  • Transplant patients

Other primary TMA syndromes include the following:

  • Shiga toxin-mediated hemolytic uremic syndrome (HUS, usually with bloody diarrhea and associated with Escherichia coli 0157: H7)
  • Complement-mediated HUS (previously referred to as atypical HUS)
  • Drug-induced TMA: Chemotherapy (mitomycin and gemcitabine), cyclosporine, tacrolimus, bevacizumab, illegal narcotics.

Enhancing Healthcare Team Outcomes

TTP is a serious life-threatening disorder that is best managed by an interprofessional team that includes a nurse, hematologist, emergency department physician, nephrologist, neurologist and an internist. Besides steroids, many of these patients may benefit from plasmapheresis. Hence, the role of the nurse cannot be understated. Monitoring for response is essential to determine the duration of plasma exchange. Typically, hemolysis markers are checked daily. Plasma exchange usually is stopped once the platelet levels stabilize at above 150 for more than 48 hours. The outcomes of patients with TTP depend on age, presence of neurological deficits, renal dysfunction, response to treatment and other co-morbidity. Most patients require a prolonged stay in hospital as recovery is gradual.[21][22] (Level V)


Article Details

Article Author

Michael Stanley

Article Author

Robert Killeen

Article Editor:

Joel Michalski

Updated:

8/27/2021 10:21:56 AM

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